Diminished systemic and antigen-specific type 1, type 17, and other proinflammatory cytokines in diabetic and prediabetic individuals with latent Mycobacterium tuberculosis infection

Abstract

Background: Diabetes mellitus type 2 (DM) is known to be a major risk factor for the development of active tuberculosis, although its influence on latent Mycobacterium tuberculosis infection (hereafter, "latent infection") remains poorly characterized.

Methods: We examined circulating plasma cytokine levels in individuals with latent infection with DM or pre-DM (ie, intermediate hyperglycemia) and compared them to levels in patients with latent infection and normal glycemic control.

Results: In persons with DM or pre-DM, latent infection is characterized by diminished circulating levels of type 1 (interferon γ, interleukin 2, and tumor necrosis factor α) and type 17 (interleukin 17F) cytokines. This was associated with decreased systemic levels of other proinflammatory cytokines (interleukin 1β and interleukin 18) and the antiinflammatory cytokine interleukin 10 but not with decreased systemic levels of type 2 cytokines. Moreover, latently infected individuals with DM had diminished levels of spontaneous and M. tuberculosis antigen-specific levels of type 1 and type 17 cytokines when antigen-stimulated whole blood was examined. Finally, there was no significant correlation between the levels of any of the cytokines measured (with the exception of interleukin 22) with hemoglobin A1c levels.

Conclusions: Our data reveal that latent infection in the presence of DM or pre-DM, is characterized by diminished production of cytokines, implicated in the control of M. tuberculosis activation, allowing for a potential immunological mechanism that could account for the increased risk of active tuberculosis in latently infected individuals with DM.

Keywords: bacterial; cytokines; diabetes; pre-diabetes; tuberculosis.

Figure 1.

Systemic levels of type 1 (interferon γ [IFN-γ], tumor necrosis factor α [TNF-α], and interleukin 2 [IL-2]; A), type 17 (interleukin 17A [IL-17A], IL-17F, and interleukin 22 [IL-22]; A), type 2 (interleukin 4 [IL-4], interleukin 5 [IL-5], and interleukin 13 [IL-13]; B), regulatory (interleukin 10 [IL-10] and transforming growth factor β [TGF-β]; B), interleukin 1 (IL-1)–family (IL-1α, IL-1β, and interleukin 18 [IL-18]; C), and other proinflammatory (interleukin 6 [IL-6], interleukin 12 [IL-12], and granulocyte-macrophage colony-stimulating factor [GM-CSF]; C) cytokines in individuals with latent Mycobacterium tuberculosis infection concomitant with diabetes mellitus type 2 (DM; n = 30), concomitant with pre-DM (n = 30), or without DM (n = 30). Cytokine levels were measured by enzyme-linked immunosorbent assay. Each circle represents a single individual, and each bar represents the geometric mean. P values were calculated using the Kruskal–Wallis test with Dunn multiple comparisons. *P < .05, **P < .01, and ***P < .001.

Figure 2.

Mycobacterium tuberculosis antigen–stimulated and unstimulated levels of type 1 (interferon γ [IFN-γ] and tumor necrosis factor α [TNF-α]), type 17 (interleukin 17A [IL-17A]), and interleukin 1 (IL-1)–family (IL-1β) cytokines and interleukin 10 (IL-10) in whole-blood specimens from a subset of 22 individuals with latent M. tuberculosis infection concomitant with diabetes mellitus type 2 (LDM) and 22 with latent infection and no DM (LNDM). Cytokines were unstimulated (A), stimulated with M. tuberculosis antigen (B), or stimulated with mitogen (C), and levels were measured by enzyme-linked immunosorbent assay in. The M. tuberculosis antigen– or mitogen-stimulated cytokines are shown as net cytokine levels with the baseline level subtracted out. Each circle represents a single individual, and bars represent geometric means. P values were calculated using the Mann–Whitney test.

Figure 3.

Relationship between systemic levels of type 1 (interferon γ [IFN-γ], tumor necrosis factor α [TNF-α], and interleukin 2 [IL-2]), type 17 (interleukin 17A [IL-17A], IL-17F, and interleukin 22 [IL-22]), and interleukin 1 (IL-1)–family (IL-1α, IL-1β, and interleukin 18 [IL-18]) cytokines and hemoglobin A1c (HbA1c) levels in 60 individuals with latent Mycobacterium tuberculosis infection concomitant with diabetes mellitus type 2 (DM) or pre-DM. Each circle representing a single individual, and the bar represents the geometric mean. P values were calculated using the Spearman rank correlation.

Figure 4.

Systemic levels of type 1 (interferon γ [IFN-γ] and tumor necrosis factor α [TNF-α]), type 17 (interleukin 17A [IL-17A] and interleukin 22 [IL-22]), and interleukin 1 (IL-1)–family (IL-1β and interleukin 18 [IL-18]) cytokines in 30 individuals with latent Mycobacterium tuberculosis infection concomitant with diabetes mellitus type 2 (LDM), 30 without latent infection and with DM (NLDM), and 30 without both latent infection and DM (NLNDM). Plasma levels were measured by enzyme-linked immunosorbent assay. Each circle representing a single individual, and each bar represents the geometric mean. P values were calculated using the Kruskal–Wallis test with Dunn multiple comparisons. *P < .05, **P < .01, ***P < .001, and ****P < .0001.